RPS6KA2, a putative tumour suppressor gene at 6q27 in sporadic epithelial ovarian cancer
RPS6KA2, a putative tumour suppressor gene at 6q27 in sporadic epithelial ovarian cancer
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DOI：
10.1038/sj.onc.1209827
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发表时间：
2007-02-01
期刊：
影响因子：
8
通讯作者：
Ganesan, T. S.
中科院分区：
文献类型：
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作者：
Bignone, P. A.;Lee, K. Y.;Ganesan, T. S.
我们先前通过等位基因丢失研究确定了6 q27（D 6S 264和D 6S 297之间）的最小区域包含推定的肿瘤抑制基因。p90核糖体S6激酶-3基因（p90 Rsk-3，RPS 6 KA 2）定位于此区间。是一种丝氨酸-苏氨酸激酶，在促分裂原活化蛋白激酶途径下游发出信号。它在正常卵巢上皮中表达，而在肿瘤或细胞系中减少或缺失。我们发现RPS 6 KA 2在卵巢中单等位基因表达，表明单个表达等位基因的缺失足以导致癌细胞中表达的完全缺失。此外，我们已经鉴定了具有替代起始密码子的RPS 6 KA 2的两种新亚型。在两个细胞系中的RPS 6 KA 2基因内鉴定出纯合缺失。RPS 6 KA 2在卵巢癌细胞系中的重新表达抑制了集落形成。在UCI 101细胞中，RPS 6 KA 2的表达降低了增殖，导致G1期阻滞，增加了凋亡，降低了磷酸化细胞外信号调节激酶的水平，并改变了其他细胞周期蛋白。相反，针对RPS 6 KA 2的小干扰RNA在41 M细胞中显示出相反的效果。上述结果表明，RPS 6 KA 2是一个假定的肿瘤抑制基因，以解释等位基因丢失在6 q27。
We had previously defined by allele loss studies a minimal region at 6q27 (between D6S264 and D6S297) to contain a putative tumour suppressor gene. The p90 ribosomal S6 kinase-3 gene (p90 Rsk-3, RPS6KA2) maps in this interval. It is a serine-threonine kinase that signals downstream of the mitogen-activated protein kinase pathway. It is expressed in normal ovarian epithelium, whereas reduced or absent in tumours or cell lines. We show that RPS6KA2 is monoallelically expressed in the ovary suggesting that loss of a single expressed allele is sufficient to cause complete loss of expression in cancer cells. Further, we have identified two new isoforms of RPS6KA2 with an alternative start codon. Homozygous deletions were identified within the RPS6KA2 gene in two cell lines. Re-expression of RPS6KA2 in ovarian cancer cell lines suppressed colony formation. In UCI101 cells, the expression of RPS6KA2 reduced proliferation, caused G1 arrest, increased apoptosis, reduced levels of phosphorylated extracellular signal-regulated kinase and altered other cell cycle proteins. In contrast, small interfering RNA against RPS6KA2 showed the opposite effect in 41M cells. The above results suggest that RPS6KA2 is a putative tumour suppressor gene to explain allele loss at 6q27.